US7618613B2 - Method for radiolabeling antibodies with yttrium-90 - Google Patents
Method for radiolabeling antibodies with yttrium-90 Download PDFInfo
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- US7618613B2 US7618613B2 US11/760,503 US76050307A US7618613B2 US 7618613 B2 US7618613 B2 US 7618613B2 US 76050307 A US76050307 A US 76050307A US 7618613 B2 US7618613 B2 US 7618613B2
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- 239000008223 sterile water Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000007675 toxicity by organ Effects 0.000 description 1
- 231100000155 toxicity by organ Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 201000011531 vascular cancer Diseases 0.000 description 1
- 206010055031 vascular neoplasm Diseases 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 108010026050 yttrium-90-DOTA-peptide-chimeric L6 Proteins 0.000 description 1
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Abstract
Description
- 1. 2B8-MX-DTPA, IDEC; Lot#082395RM2
- 2. 50 mM Sodium Acetate, low-metal, IDEC; Lot#082395RM3
- 3. Formulation Buffer (1×PBS, pH 7.4 containing 7.5% (w/v) human serum albumin and 1 mM DTPA), IDEC, Lot#082395RM1
- 4. Reaction vial, 10 mL, IDEC
B. Materials and Equipment - 1. Biodex Tec-Control Radioincorporation Kit, Cat.#151-770
- 2. Gloves: powder-free
- 3. Sterile polypropylene syringes
- 4. Sterile syringe needles
- 5. Small tubes with closure; 1.5 ml
C. Methods
- 1. Yttrium-[90]: chloride salt, carrier-free, in HCl.
Precautions:
1. All steps should be performed using aseptic technique.
2. Radiolabeling kit components should be allowed to come to room temperature before use.
Radiolabeling Protocol
1. The volume of 90YCl3 to add to the reaction vial was calculated as follows:
-
- C0=Radioactivity concentration at time of calibration (see manufacturer's Certificate of Analysis).
- Δt=Change in time (positive number is post calibration, negative number is pre calibration).
2. The volume of 50 mM sodium acetate to add to the reaction vial was calculated as follows:
-
- a. For 90YCl3 in 0.040 M HCL (Amersham):
- Volume 90YCl3 (Step 1b)×(0.8)=volume of sodium acetate to add
- b. For 90YCl3 in 0.050 M HCl(Nordion):
- Volume 90YCl3 (Step 1b)×(1.0)=volume of sodium acetate to add
3. The septa of the reaction vial and the sodium acetate vial were wiped with alcohol. Using a 1 cc syringe, the calculated volume (Step 1a or 1b) of 50 mM sodium acetate (Step 2) was transferred to the reaction vial. The vial was mixed by inverting several times.
4. The septum of the 90YCl3 source vial was wiped with alcohol. The vial with a needle fitted with sterile 0.2 μm filter. Using a 1 cc sterile syringe, was vented the required volume (Step 1b) of 90YCl3 was transferred to the reaction vial. The vial was mixed by inverting several times.
5. The septum of the 2B8-MX-DTPA vial was wiped with alcohol. Using a 3 cc sterile syringe, 1.5 mL of 2B8-MX-DTPA was transferred to the reaction vial. The vial was mixed by inverting several times.
6. The total volume of reaction mixture was calculated by adding the amount of Y-90 chloride added (Step 4), plus the amount of 50 mM sodium acetate added (Step 3), plus the amount of 2B8-MX-DTPA added (Step 5).
7. The volume of Formulation Buffer to add to the Reaction Vial to obtain a final volume of 10 mL was calculated by subtracting the total reaction volume calculated instep 6 from 10.
8. The Formulation Buffer vial was wiped with alcohol and the vial was vented. Due to the viscosity of the Formulation Buffer, the reaction vial using a needle fitted with a 0.20 μm syringe filter. Using a 10 cc sterile syringe fitted with an appropriate gauge needle, the volume of Formulation Buffer calculated in Step 7 was transferred to the reaction vial. The vent needle was removed from the reaction vial and the vial was mixed by inverting several times (Final Product). The vial was incubated at least 5 minutes prior to doing the “Radioincorporation Assay”. The color of the solution was amber and the reaction vial was full thereby confirming that Formulation Buffer was added.
9. The total radioactivity of the Final Product vial was measured using the appropriate instrumentation set for measurement of 90Y.
10. The Final Product was immediately stored at 2°-8° C. until required for patient administration.
4. Each section was counted for activity using an appropriate counter, i.e., a scintillation counter for 90Y, adjusting for background.
5. The Biodex instructions for calculating the percentage of radiolabeled antibody were followed.
- 1. The radiolabeled antibody stored at 2°-8° C. was obtained.
- 2. A volume of 10 μL was withdrawn with a P20 and added to a 1.5 mL microfuge tube containing 990 μL of Dilution buffer (1:100 dilution). The tip was rinsed and the tube was vortexed slightly.
- 3. A 50 mL sterile polypropylene tube with h cap was obtained and 10 mL of Dilution buffer to the tube, using a 10 mL serological pipette.
- 4. A volume of 35 μL was withdrawn with a P200 from the 1:100 dilution tube and added to the conical tube containing 10 mL of Dilution buffer. Mix thoroughly.
Lyophilized Cell Prep - 1. Three tubes of lyophilized SB Cells were obtained.
- 2. A volume of 0.5 mL of SWFI was added to each tube, and the tubes were vortexed until single cell suspensions were obtained.
- 3. Three empty 1.5 mL microfuge tubes were obtained; to three of the tubes, 0.5 mL of Dilution buffer was added, representing a control with no cells. Assay Protocol
- 1. A volume of 0.5 mL of the diluted 90Y2B8-MX-DTPA was added to each tube.
- 2. The tubes were placed on end over mixer for 45 minutes, after making sure caps are securely tightened.
- 3. After 45 minutes incubation at ambient temperatures the cells were pelleted by microcentrifugation for 5 minutes.
- 4. A volume of 0.8 mL of the supernatant was transferred to scintillation vials.
- 5. Scintillation cocktail was added to each vial.
- 6. The amount of radioactivity in each vial was determined using a scintillation counter, adjusting for background.
D. Results
-
- #1: IDEC Pharmaceuticals
- #2: IDEC Pharmaceuticals
- #3: IDEC Pharmaceuticals
- #4: MD Anderson Health Center
- #5: Mayo Clinic
- #6: City of Hope
The results of testing on each validation lot are summarized in Table 1.
TABLE 1 |
Release Assay Results for Y2B8 Validation |
Lot Number | % Radioincorporation | % Binding |
1 | 99.5 | 78.6 |
2 | 99.3 | 87.0 |
3 | 99.4 | 85.9 |
4 | 99.2 | 81.8 |
5 | 99.2 | 79.6 |
6 | 96.3 | 80.8 |
Mean = 98.8 | Mean = 82.3 | |
Standard Deviation = 1.24 | Standard Deviation = 3.4 | |
% CV = 1.25% | CV = 4.2% | |
TABLE 2 |
Y2B8 Radiolabeling Kinetics: Effect of pH on Radioincorporation |
and Binding to CD20-Positive Cells1 |
Reaction pH | Radioincorporation (%) | Binding (%) |
3.9 | 98.4 | 80.7 |
4.2 | 97.8 | 81.0 |
4.4 | 96.1 | 80.0 |
4.6 | 97.0 | 80.2 |
4.7 | 97.4 | 80.6 |
TABLE 3 |
Y2B8 Radiolabeling Kinetics: Effect of Incubation Time on |
Radioincorporation and Binding to CD20-Positive Cells1 |
Incubation Time (min) | Radioincorporation (%) | Binding (%) |
pH 3.9: | 3 | 97.0 | 82.0 |
5 | 98.9 | 82.1 | |
10 | 99.2 | 82.3 | |
pH 4.7: | 3 | 97.2 | 82.5 |
5 | 96.7 | 81.8 | |
10 | 97.6 | 81.5 | |
1The labeling reaction results and parameter evaluation studies reported in Tables 2 and 3 were performed with 2B8 derived from, a CHO cell expression system; The MX-DTPA conjugate was using a protocol similar to that used for the previously characterized 2B8-49. Reactions were performed using approximately 3 mg of antibody and a 4:1 molar ratio of chelator to antibody as described in co-owned, copending application Ser. No. 09/ , concurrently filed and herein incorporated by reference. |
TABLE 4 | ||
Predicted | ||
Predicted Effect on | Effect on | |
Radiolabeling Kit Deviation | Labeling Conditions | Binding |
1.) Adding Excess Volume of 90Y | decrease pH; | |
increase radiolysis | ||
2.) Adding Less Volume of 90Y | no change in pH; | increase |
decrease radiolysis | or |
|
3.) Adding Excess Volume of NaAc | no change in pH; | increase |
decrease radiolysis | or |
|
4.) Adding Less Volume of NaAc | decrease pH; | |
increase radiolysis | ||
5.) Adding Excess Volume of | no change in pH; | increase |
2B8-MX-DTPA | decrease radiolysis | |
(lower specific | ||
activity) | ||
6.) Adding Less Volume of | no change in pH; | decrease |
2B8-MX-DTPA | increase radiolysis | |
(higher specific | ||
activity) | ||
7.) Incubating >5 min. | increase radiolysis | decrease |
8.) Incubating <5 min. | decrease radiolysis | increase |
or none | ||
- 1. 90YCl3 in 0.05 M HCL; Pacific Northwest National Laboratory, reagent grade; P.O.#08016, 08118
- 2. Ultrex HCL; J. T. Baker, Product#6900, Lot# J22539
- 3. Sterile Water for Irrigation; Baxter, Part#2F7114, Lot# G924092
- 4. Dilution Buffer; contains 10 mM phosphate buffered saline, pH 7.4, 1% BSA; Sigma, Part# P-3688, Lot#076H8913
- 5. IDEC Supplied Radiolabeling Kit; IDEC Part#130018, Lot#0129, containing the following:
- a.) 2B8-MX-DTPA; IDEC Part#129017, Lot#0165
- b.) 50 mM Sodium Acetate; IDEC Part#121017, Lot#0209A
- c.) Formulation Buffer; IDEC Part#120015, Lot#0202
- d.) Reaction Vial; IDEC Part#122015, Lot#0218
- 6. Lyophilized SB Cells, IDEC Part#127, Lot#127-001F
B Materials and Equipment - 1. Pipettors (20, 200 and 1000 gL)
- 2. Vortexer
- 3. Metal-Free Pipette Tips (Biorad; metal-free)
- 4. Gamma Counter (Isodata, Model#20-10)
- 5. Glass Tubes (12×75 mm)
- 6. Polypropylene Tubes (Costar; 15 mL and 50 mL conical, sterile)
- 7. Tec-Control Radiochromatographic Kit (Biodex; Cat#151-770)
- 8. Microcentrifuge (Savant)
- 9. Polypropylene microfuge tubes, metal-free (Biorad; Cat#223-9480)
C. Methods
1. Preparation of Y2B8
TABLE 5 |
Volume of Reagents (mL) |
90Y Amount (mCi) | 90Y Chloride | Sodium Acetate | 2B8-MX- |
1 | 0.0119 | 0.0143 | 0.0333 |
3 | 0.0357 | 0.0429 | 0.0998 |
10 | 0.119 | 0.143 | 0.333 |
40 | 0.476 | 0.571 | 1.33 |
TABLE 6 | ||
Amount of 90Y mCi | % of Control Binding | |
1 | 100 | 99.2 |
3 | 102 | 99.1 |
10 | 98.6 | 99.0 |
40 | 98.2 | 99.0 |
2. Impact of Adding Less Volume of Sodium Acetate
TABLE 7 | |||
Monday Dose Preparationa | Friday Dose Preparationb |
% of Binding | % | % of Binding | % | |
Labeling Deviation | Controlb | Radioincorporation | Controlb | Radioincorporation |
1.) | 20% Less | 89.4 | 99.1 | 92.5 | 98.7 |
Volume of | |||||
| |||||
2.) | 60% Increase in | ||||
Reaction Time | |||||
(8 min.) | |||||
1.) | 20% Excess | 90.6 | 99.1 | 91.8 | 98.6 |
Volume of 90 | |||||
2.) | 60% Increase in | ||||
Reaction Time | |||||
(8 min.) | |||||
1.) | 20% Less | 98.9 | 99.0 | 98.7 | 98.6 |
Volume of | |||||
| |||||
2.) | 60% Increase in | ||||
Reaction Time | |||||
(8 min.) | |||||
aFor a Monday dose preparation, the concentration of 90Y in the reaction solution is 17 mCi/mL; the 90Y concentration for a Friday labeling is 8 mCi/mL. | |||||
Binding values normalized to labeled antibody prepared according to clinical dose protocol (RSBR-005) using “standard” reagent volumes and a 5 min. reaction time. |
5. Impact of Combined Reagent Deviations
TABLE 8 | ||
Labeling Time (min.) | % of Binding Control | % Radioincorporation |
|
2 | 97.6 | 98.7 |
4 | 93.7 | 98.8 |
6 | 89.5 | 98.8 |
8 | 83.2 | 98.6 |
|
2 | 98.6 | 99.0 |
4 | 98.5 | 99.2 |
6 | 96.0 | 99.1 |
8 | 92.1 | 99.1 |
V. Discussion
- M. W. Brechbiel et al., “Synthesis of C-Functionalized trans-Cyclohexyldiethylenetriaminepenta-acetic Acids for Labelling of Monoclonal Antibodies with the Bismuth-212 α-Particle Emitter”, J. Chem. Soc. Perkin Trans., pp. 1173-1178, 1992
- M. E. Izard et al., “An Improved Method for Labeling Monoclonal Antibodies with Samarium-153: Use of the Bifunctional Chelate 2-(p-Isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic Acid”, Bioconjugate Chem., 3(4):346-350, 1992.
- R. B. Huneke et al., “Effective α-Particle-mediated Radioimmunotherapy of Murine Leukemia1”, Cancer Research, 52:5818-5820, 1992
- O. A. Gansow et al., “Macrocyclic or Conventional Ligands? Selection of Effective Chelators for 90Y or 212Bi Radioimmunotherapy”, Chemistry Section, Radiation Oncology Branch, Metabolism Branch, National Cancer Institute
- S. Mirzadeh1,2 et al., “The Chemical Fate of 212Bi-DOTA Formed by β− Decay of 212Pb(DOTA)2−*′**”, Radiochimica Acta 60:1-10, 1993
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US11/181,811 US7229620B2 (en) | 1999-03-01 | 2005-07-15 | Method for radiolabeling antibodies with yttrium-90 |
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US20020102208A1 (en) * | 1999-03-01 | 2002-08-01 | Paul Chinn | Radiolabeling kit and binding assay |
AU2001296507A1 (en) | 2000-10-02 | 2002-04-15 | Chiron Corporation | Human anti-cd40 antibodies |
US6696060B2 (en) * | 2001-06-14 | 2004-02-24 | Clearant, Inc. | Methods for sterilizing preparations of monoclonal immunoglobulins |
US7252799B2 (en) | 2001-08-31 | 2007-08-07 | Clearant, Inc. | Methods for sterilizing preparations containing albumin |
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US6974563B2 (en) | 2002-06-18 | 2005-12-13 | Lynntech, Inc. | Ion exchange materials for the separation of 90Y from 90SR |
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